PROJECT 1 ? Gene x Stress interactions' impacts on pathways to cardiometabolic disease PROJECT SUMMARY Our program, developed over 25 years of NHLBI support, has identified and continues to identify gene variants that interact with psychosocial stress to influence, via central nervous system and peripheral mechanisms, expression of behavioral and physiological endophenotypes in pathways to cardiometabolic disease and adverse clinical course. During the renewal period Project 1 will extend and substantially refine this work. Among the major challenges in studying gene by stress interactions are the need for a large number of individual observations in order to yield adequate statistical power and precision, and the relative absence of explicit measures of stress in prior studies. Project 1 addresses the first challenge by, in collaboration with the Biostatistics and Bioinformatics Core, harmonizing a number of large existing datasets, which will in turn be used to validate previous and newly discovered findings (Aim 1), and to embed those findings in the broader context of race (African Americans and Caucasians) (Aim 2) and potential mediating mechanisms that are thought to link variants to cardiometabolic disease. Project 1 overcomes the absence of explicit measures of stress by constructing a synthetic index of stress using bioinformatics techniques, which have proven successful in our preliminary work. We also will continue our discovery approach using high-throughput computational bioinformatics approaches, and gene x stress GWAS will be used in large publically accessible databases (e.g., MESA, FHS, CARDIA. Jackson Heart Study) to identify new gene variants associated with cardiometabolic endophenotypes (Aim 3). These newly discovered variants will be validated in new data derived from the harmonization. Project 1 also will pass previously and newly identified gene variants associated, both directly and via interaction with stress, with cardiometabolic endophenotypes to Project 2 (to test for effects on endophenotypes in pathways to type 2 diabetes), Project 3 (to test for effects on epigenetic, transcriptomic and metabolomics mechanism that mediate effects on endophenotypes and disease endpoints), and Project 4 (to test for effects on response of endophenotypes to behavioral and drug interventions). Successful completion of these aims will increase our understanding of gene x stress interactions that link stress to the development and course of cardiometabolic disease, knowledge that will be critical for the ultimate development of effective preventive and treatment interventions.